N-methyl quaternary derivatives of morphinan alkaloid such as naltrexone ((5α)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one, sometimes referred to as N-cyclopropylmethyl-noroxymorphone) and naloxone (5α)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one, sometimes referred to as N-allyl-noroxymorphone) have useful pharmacological properties as potent antagonists of the μ receptor. They bind to peripheral receptors primarily located in the gastrointestinal tract, act as antagonists and effectively mitigate some of the undesirable side effects of opiate therapy such as constipation and nausea. Because of their ionic charge, however, they do not traverse the blood brain barrier into the central nervous system; hence, the central activity of opiates responsible for pain relief is not blocked in the presence of these quaternary derivatives.
In U.S. Pat. No. 4,176,186, Goldberg et al. generally describe the preparation of quaternary derivatives of certain morphinan alkaloid by quaternizing a tertiary N-substituted morphinan alkaloid with a methylating agent such as methyl bromide, methyl iodide or dimethylsulfate. Goldberg et al. disclose that the methylating agent itself may be used as the solvent or, alternatively, another solvent medium such as methanol, ethanol, or other alcohols, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetronitrile, nitromethane or hexamethylphosphoric triamide may be used.
In WO 2004/043964 A2, Cantrell et al. disclose a process for the preparation and/or recovery of quaternary morphinan alkaloids. This process comprises contacting a tertiary N-substituted morphinan alkaloid with an alkyl halide in an anhydrous solvent system, wherein the solvent system comprises an aprotic dipolar solvent with the aprotic dipolar solvent constituting at least 25 wt % of the solvent system. Cantrell et al. further describe the recovery of the 3-hydroxy morphinan alkaloid by converting the alkaloid to a salt using a strong base. Examples of these strong bases comprise sodium methoxide, NaOH and KOH in methanol/water. However, the process of Cantrell et al. turned out to result in morphinan alkaloids containing considerable amounts of the alkylating agent used in the process.